Project Summary Mucommune is developing a dual-action intravaginal ring (IVR) that will provide month-long (i) non-hormonal contraception by sustained release of an ultrapotent contraceptive antibody, and (ii) prevention of bacterial vaginosis (BV) by sustained release of lactic acid (LA) to support a protective Lactobacilli-dominant microbiome. Millions of women avoid hormonal contraceptives due to medical contraindication as well as real or perceived side effects of exogenous hormones, and would have strong interest in effective non-hormonal contraceptives that do not require coitally-related interruptions. BV, a vaginal dysbiosis with polymicrobial bacterial populations, depletes protective resident Lactobacilli that would otherwise acidify the vagina with lactic acid (LA), a broad-spectrum microbicide that protects against many sexually transmitted pathogens. BV greatly increases the risks of acquiring various sexually transmitted infections such as HIV, and increases risks of premature births. There is no product on the market that can provide sustained protection against BV or convenient month-long non-hormonal contraception. To meet these challenges, we have engineered a novel ultrapotent anti-sperm antibody (MM0008) that targets a well-validated contraceptive target. MM008 agglutinates human sperm with a greater than 16-fold augmented potency compared to the parent IgG antibody, and completely agglutinated all human sperm dosed to the sheep vagina within 2 mins at just tens of micrograms dosed per sheep. Separately, we have also developed polymer matrix ring formulations that can provide sustained release of LA at rates designed to match those continuously secreted by protective vaginal Lactobacilli. These advances have enabled us to propose developing the multipurpose LA- and MM0008- releasing IVR (LA-MM008-IVR) based on our proprietary capsule-IVR platform, where embedded capsules release MM008 with near zero-order kinetics for one month, while protecting MM008 from LA. The ring is made with a carefully optimized blend of polymer matrix that releases LA at rates likely needed for month-long protection against BV. This unique capsule-IVR design allows us to independently tune the release of LA and MM008, and is easy to manufacture at very low cost and high throughput, which in turn should maximize potential public health impact and commercial viability of the product both in the U.S. and in low- and middle-income countries worldwide. In Specific Aim 1, we will prepare a number of LA-MM008-IVR formulations, and perform rigorous in vitro characterizations quantifying the rate of LA and MM008 release over time. In Specific Aim 2, we will first determine the highest tolerable dose of LA in sheep, which is anatomically similar to the human vagina, followed by vaginal pharmacokinetic study to assess the release of LA and MM008 from the lead LA-MM008- IVR formulation. Successful demonstration of safety and efficacy in this highly relevant anima...